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Multi-Purpose Microreactors
A Fast Track to Optimized Processes?
Standard batch reactors have long been the workhorse for chemical ingredient and intermediate manufacturing and,
although their use is well understood, they do have a number of performance drawbacks and limitations such as poor
mixing, limited heat transfer capabilities, and lengthy scale-up phases. These limitations have led to the evaluation of
alternative production methods with microreactors, in many instances, offering a more effective solution for chemical
manufacture and great potential as a ‘fast track’ to optimized processes.

Extensive research work using microreactors has been undertaken by SAFC®. This work resulted in both the successful
execution of a number of reactions not possible in traditional batch processors and, depending on the process and batch size,
more cost-effective reactions for processes that already run well in batch reactors.

Microreactors are not new. In fact, they have been around in various forms since the end of the 19th Century. However, it is
only very recently that their full range of uses are being fully explored and employed in the production of fine chemicals on a
bulk scale. Microreactors are generally made from stainless steel or glass, and each material offers different benefits. Glass,
for example, is more chemically resistant and therefore ideal for multipurpose work, while stainless steel has better heat
conductivity, so is preferable for very exothermic reactions. Stainless steel is also more robust than glass, so in many cases it
will be the ideal choice for a production environment if the reaction is compatible.

The Nature of Microreactors

Many lab reactions are not suitable for large scale
processing, the most common problems being that the
reagents are too dangerous in bulk or the reaction requires
specific conditions, such as low temperature that are hard to
achieve in large reactors. Another problem is that, in many
cases, development chemists find that a reaction that is
effective at the small-scale lab level simply does translate
to work on a large scale. Unlike batch reactors, where
fixed quantities of reagents are mixed together for a pre-
determined length of time before the reaction is worked up,
microreactors offer continuous processing, so the production
of larger quantities is simple – the microreactor runs for a
longer period of time. This is an important distinction for
process development, as it means that the same reaction
parameters and equipment can be easily and appropriately
scaled up from lab-scale to and large-scale production.
Traditional batch chemistry, on the other hand, usually
requires additional process development as larger batch
sizes and vessels are used.
In a microreactor, as the equipment is the same throughout,
the same person can be responsible for the whole process
optimization, from the first trial runs to the final production.
The first step of this process is to identify the best solvent.
This is one of the most critical parameters for a continuous
process, as it is essential that all the components remain in
solution throughout their time within the reactor. The ideal
concentration and flow rate combination also need to be
established to maximise the yield and speed of the process.
The flow rate at which the reactants are pumped through
the channel is an important factor as it determines how long
the chemicals remain within the microreactor chambers.
Too fast and the reaction will not go to completion, but if it’s
too slow productivity is poor. Once these steps have been
carried out, multi-kilogramme quantities can be manufactured.
Ingredients are pumped into a narrow tube or channel,
which is typically around 200µm in diameter. It is here that
the reaction takes place, and only very small quantities of
reagents are ever in the reactor at the same time.

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Figure 1: Microreation Technology

Regulation
Unit
Pressure Temperature
control control

Micro Residence
Reagent 1 Reactor Time
Unit Product

Reagent 2
0.2-2mL to 200mL

Heat Transfer

Heat transfer is one of the biggest issues when scaling up an
exothermic reaction to a large batch reactor. In a standard
100ml flask in the lab, for example, the surface-to-volume
ratio is good, which makes it relatively straightforward to
control the temperature of an exothermic reaction by
dissipating it through the sides of the flask. However, when
this is scaled up to a 1000 litre reactor, the surface-to-volume
ratio drops to just 6% of that of the flask. This makes it much
more difficult to remove the heat generated in the reaction. In
contrast, if the reaction takes place in a typical microreactor
with 200µm channels, the surface-to-volume ratio is 200 times
greater than for the 100ml flask, so heat transfer is unlikely to
be an issue. This increased temperature control also means
that ‘hot spots’ are less likely.
When a reagent for an exothermic reaction is dropped into a
batch reactor, it forms a hot spot where it lands and heat is
created by the reaction. This needs to be dissipated, and is
usually done so by stirring. However, the localized increase
in temperature – even if it’s only a couple of degrees – can
lead to unwanted side-products being formed because of the
elevated temperature. In contrast, because volumes are so
small in a microreactor, it is significantly easier to maintain
a narrow temperature window so that the side-products that
may be formed at a higher temperature are less likely to pose
problems.

Figure 2: Heat Transfer - Optimal Mixing

Vessel Microreactor

Concentration profiles:

MRT Channel
Reactor size 1000lt Reactor 250lt Reactor 0.1lt Flask
size 200um
Surface/Volume 0.06 0.08 1 200

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Working with Hazardous Reagents
As microreactors operate on a small scale, many reactions
that process development chemists would normally classify
as too dangerous or difficult to work with in a batch reactor,
for example those which are highly exothermic, can be
run safely. Microreactors also make it possible to use
reagents that, while commonplace in the lab, are much too
dangerous on a large scale. Diketene, for example, is one
such substance which, although a very useful and versatile
building block, is highly reactive and as such could only
be used in batch reactors with difficulty and limitations. By
carrying out reactions in a microreactor, the volume of the
hazardous reagent in the active reaction zone is kept to a
minimum.
Precise Temperature Controls
Precise temperature control permits much better process
control enhancing overall safety. It also becomes more
practical to use reactions that involve unstable intermediates.
N-Butyl lithium is a common reagent used in the lab which
must be used at very low temperatures, and, when used in
a batch reactor, requires cryogenic techniques with cooling
jackets used to keep the temperature at very low levels
(usually –70°C), significantly increasing installation costs.
This increased cost can be nullified by using a sequence
of microreactors instead. As an example, in the two step
substitution reaction shown in Figure 3 below, n-BuLi in
heptane was first used to monolithiate 1,4-dibromobenzene,
with the reaction completed in less than 90 seconds in the
first microreactor, where the temperature is kept at 0°C.
Figure 3: Example of a Two -Step Substitute Reaction
BuLi F3C–CO2Et O scale synthesis. However, this will require that manufacturers
Br Br Li Br
F3C
Product 18550
Due to the short contact time, this elevated temperature did
not cause decomposition and also saved costs since there
was no need for cryogenic equipment. The reaction mixture
was then transferred into a second microreactor, along with
a coupling reagent, ethyl trifluoroacetate. Again, this reaction
was carried out at 0°C, taking 60 seconds to complete.
Finally, this mixture was transferred into a ‘residence time
unit’ at room temperature to bring the reaction to completion.
Not only does this setup remove the need for expensive
cryogenic equipment, it offers several other advantages over
batch production in that it gives consistent product quality
through a reduction in batch to batch variation and limited
single-batch productivity. In addition, there were fewer side
products resulting from competing reactions such as double
lithiation and Wurtz coupling, which commonly take place at
hot spots at the drop-in site within the batch reactor.
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Optimized Use of Space
One final and significant advantage of continuous processing
using microreactors is that the reactors themselves take up
far less floor space than traditional batch vessels, meaning
that more of them could be used if required in a smaller
overall footprint, thus increasing productivity and output.
Although a sizeable vessel will still be required for product
collection, and further work-up and purification procedures
are often required, the space and equipment requirements
for the reactors themselves are lower. A typical microreactor
used in production is about half a metre high and wide, and
approximately 30cm (10”) deep. With a medium flow rate
and rapid reaction time, at SAFC this has resulted in actual
microreactor production rates of 15 tonnes per annum. Much
higher rates are also possible and, because the volumes of
reagents within the reactor at any one time are so small, the
need for explosion proof cabinets is minimized.
Perhaps the single most important advantage of
microreactors is their flexibility. Known microreactor
productivity allows one to calculate the time required to
manufacture the required amount of product, rather than
determine the most efficient batch reactor and determine
the number of batch runs necessary for the same amount of
product.
In conclusion, microreactors are now becoming more
important in the production of fine chemicals because of
their flexibility, their potential for cost savings, and the ability
to do reactions that could not be carried out in a batch
reactor due to inherent hazards. This opens up a whole new
world of chemistry to manufacturers, and will also speed up
routine development time for APIs as more applications seen
in medicinal chemistry will now be able to remain in large
Br
re-examine the best way to have large scale fine chemicals
manufactured. Chemists are trained to think in terms of batch
processing, but as they get used to the possibilities of using
continuous processing in a flow reactor, microreactors are
set to become a common tool in the manufacture of fine
chemicals.
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